The Impact of T Cell Help on Anti-dsDNA B Cells

描述（申请人提供）：抗dsDNA抗体（Abs）是一种 系统性红斑狼疮（SLE）的诊断标准。了解如何 这些自身抗体在健康个体中受到调节， 在自身免疫中表达的潜在机制，我们使用了 免疫球蛋白转基因（IG Tg）模型。这种模式的优势在于， 抗dsDNA B细胞的发展可以在一个 非自身免疫性和自身免疫易感性（lpr/lpr）中多样的B细胞库 背景我们目前的数据表明，T细胞在免疫系统中起着决定性作用。 抗dsDNA B细胞的表型。使用Ab耗竭去除CD 4细胞，我们 已经证明，抗dsDNA B细胞在 Fas缺陷小鼠--它们的卵泡进入和成熟--依赖于T 手机帮助此外，使用模型系统来提供T细胞帮助，我们可以 诱导抗dsDNA B细胞进入卵泡、成熟和产生Ab 在Fas充足的小鼠中。总的来说，这些结果表明， T细胞辅助的可用性负责确定抗dsDNA B 细胞在功能上沉默或被激活。最后，我们确定了 lpr/lpr树突状细胞（DC）的独特属性，我们假设发挥 在体内产生（自身）反应性T细胞帮助中的核心作用。 在这里，我们建议扩展这些初步调查结果，以确定第一， CD 4 T细胞的性质有助于促进年轻Fas缺陷小鼠 抗dsDNA B细胞进入滤泡但未终末分化，和 T细胞的需求有助于促进10周龄小鼠自身抗体的产生 动物我们将测试不同类型的T细胞提供T细胞的能力。 细胞有助于Fas充足小鼠中的BALB/c抗dsDNA B细胞，并改变 lpr/lpr小鼠中自身抗体产生的动力学。其次，我们将研究DC 在lpr/lpr小鼠中的功能，并确定DC的改变在多大程度上 LPR/LPR小鼠中的表型参与自身免疫的起始或 继发于T和/或B细胞的失调。定义流程， 将某些自身反应性B细胞从其耐受状态中释放出来， 对自身免疫性疾病的理解和最终治疗。

DESCRIPTION (provided by applicant): Anti-dsDNA antibodies (Abs) are one of the diagnostic criteria of systemic lupus erythematosus (SLE). To understand how these autoAbs are regulated in healthy individuals and to identify the mechanisms underlying their expression in autoimmunity, we have used an immunoglobulin transgenic (Ig Tg) model. The advantage of this model is that the development of anti-dsDNA B cells can be tracked in the context of a diverse B cell repertoire in non-autoimmune and autoimmune-prone (lpr/lpr) backgrounds. We present data showing that T cells play a determining role in the phenotype of anti-dsDNA B cells. Using Ab depletion to remove CD4 cells, we have demonstrated that the phenotypic changes in anti-dsDNA B cells in Fas-deficient mice - their follicular entry and maturation - are dependent on T cell help. Additionally, using a model system to provide T cell help, we can induce follicular entry, maturation, and Ab production from anti-dsDNA B cells in Fas-sufficient mice. Collectively, these results suggest that the availability of T cell help is responsible for determining whether anti-dsDNA B cells are functionally silent or become activated. Finally, we have identified unique attributes of the lpr/lpr dendritic cells (DCs) that we hypothesize play a central role in generating the (auto)reactive T cell help in vivo. Here, we propose to extend these preliminary findings to identify first, the nature of the CD4 T cell help in young Fas-deficient mice that promotes follicular entry but not terminal differentiation of anti-dsDNA B cells, and the requirements for T cell help in promoting autoAb production in 10-week-old animals. We will test the ability of distinct classes of T cells to provide T cell help to BALB/c anti-dsDNA B cells in Fas-sufficient mice and to alter the kinetics of autoAb production in lpr/lpr mice. Second, we will examine DC function in lpr/lpr mice, and determine the extent to which alterations in DC phenotype in lpr/lpr mice are involved in the initiation of autoimmunity or are secondary to the dysregulation of T and/or B cells. Defining the processes that release certain self-reactive B cells from their tolerant state is critical to the understanding and eventual treatment of autoimmune disease.